Levonorgestrel And Ethinyl Estradiol

Introduction Overview

Generic Name

levonorgestrel and ethinyl estradiol

Brand Name

Kurvelo

Dosage Form

tablets

Drug Class

Contraceptives

Pharmacokinetics

Absorption:
Levonorgestrel and ethinyl estradiol are rapidly and extensively absorbed from the gastrointestinal tract following oral administration of Kurvelo tablets. Ethinyl estradiol, the estrogen component, exhibits rapid absorption with peak plasma concentrations typically attained within 1 to 2 hours post-dose. Levonorgestrel, the synthetic progestin, reaches peak plasma concentrations approximately 1.5 to 4 hours after ingestion. The absolute bioavailability for ethinyl estradiol is approximately 43%, due to significant first-pass hepatic metabolism, while levonorgestrel has a bioavailability of approximately 95%. Factors such as gastrointestinal motility, presence of food, and gastrointestinal disturbances (e.g., vomiting or diarrhea within 3 to 4 hours of dosing) may reduce absorption and consequently contraceptive efficacy.

Distribution:
Both levonorgestrel and ethinyl estradiol exhibit extensive plasma protein binding; levonorgestrel binds primarily to sex hormone-binding globulin (SHBG) and albumin, while ethinyl estradiol binds mainly to albumin. Levonorgestrel's binding to SHBG enhances its half-life and modulates biological activity. The volume of distribution (Vd) for levonorgestrel is approximately 1.8 to 2.8 L/kg, reflecting widespread tissue distribution. Ethinyl estradiol distributes broadly into body tissues, including target reproductive organs. Estrogen administration increases serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin, potentially altering the levels of binding proteins and necessitating dose adjustments for thyroid or cortisol replacement therapies.

Metabolism:
Levonorgestrel undergoes extensive hepatic metabolism primarily via reduction, hydroxylation (mediated by cytochrome P450 3A4), and conjugation to form inactive metabolites eliminated by renal and biliary pathways. Ethinyl estradiol is metabolized predominantly in the liver by oxidative hydroxylation via CYP3A4 and subsequent conjugation through sulfation and glucuronidation. The presence of enzyme inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) may increase metabolism of both components, reducing plasma concentrations and contraceptive efficacy. Conversely, CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, grapefruit juice) may elevate systemic exposure, increasing risk of adverse effects.

Elimination:
Levonorgestrel's elimination half-life ranges from approximately 25 to 50 hours. Metabolites are excreted via urine and feces. Ethinyl estradiol has a half-life of approximately 15 to 27 hours, with excretion of conjugated metabolites in urine and bile. Continuous daily dosing of Kurvelo leads to steady-state plasma concentrations within 3 to 5 days. Renal or hepatic impairment can affect metabolism and elimination, warranting clinical monitoring. The contraceptive effect depends on maintaining adequate systemic hormone levels; thus, adherence and avoidance of interactions impacting metabolism are critical to efficacy.

Dosage Forms

Available Dosage Forms:
Kurvelo is supplied as an oral tablet formulation available as a blister pack containing 28 tablets per pack. Each pack contains 21 light-orange active tablets, each comprising 0.15 mg levonorgestrel and 30 mcg ethinyl estradiol, and 7 pink inert (placebo) tablets devoid of active hormones. Tablets are round, biconvex, approximately 6mm in diameter, with debossed imprints 'LU' and 'U31' on active tablets and 'LU' and 'U32' on inert tablets.

Dosages for Adults and Adolescents:
Recommended dosing involves oral administration of one tablet daily at the same time each day, following either a Day 1 start (first day of menstrual bleeding) or a Sunday start regimen (first Sunday after menstruation begins). For the first cycle under the Sunday start regimen, backup contraception should be used for the initial seven days. Continuous daily intake for 28 days constitutes one cycle, with the next pack started immediately after the last tablet of the prior pack, regardless of bleeding status. Missed doses should be managed according to specific guidelines based on the timing and number of tablets missed to maintain contraceptive effectiveness.

Specific Patient Populations:
Special consideration is warranted for women post-abortion or miscarriage, postpartum women, and those switching from other contraceptive methods. Kurvelo may be started immediately after first-trimester abortion or miscarriage without added contraception but should be delayed until four weeks postpartum to reduce thromboembolic risk. Breastfeeding women are advised against use, as Kurvelo may diminish milk production. Dosage adjustments are not typically required, but close clinical monitoring is advised in patients with conditions affecting liver metabolism or with genetic hypercoagulopathies.

Storage and Handling:
Kurvelo tablets should be stored at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Tablets must be protected from light and stored in their original packaging until use to maintain stability and potency.

Mechanism Of Action

Kurvelo operates as a combination oral contraceptive comprising levonorgestrel, a potent synthetic progestin, and ethinyl estradiol, a synthetic estrogen. The contraceptive efficacy primarily results from the synergistic actions of these two hormones on the hypothalamic-pituitary-ovarian axis.

Levonorgestrel exerts potent progestogenic activity, which suppresses the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby inhibiting ovulation. This suppression prevents follicular maturation and ovulation, effectively reducing the likelihood of fertilization. Additionally, levonorgestrel induces changes in the endometrium that reduce the potential for implantation and thickens cervical mucus, which acts as a barrier to sperm penetration and migration through the cervix.

Ethinyl estradiol enhances the contraceptive effect by stabilizing the endometrial lining, reducing breakthrough bleeding, and augmenting the suppression of gonadotropin secretion from the pituitary gland. This estrogenic action maintains regular withdrawal bleeding cycles and contributes to the regulation of menstrual cycles during therapy.

Together, levonorgestrel and ethinyl estradiol alter the hormonal milieu to effectively prevent pregnancy through multiple complementary mechanisms. The combined estrogen-progestin formulation also modulates the secretion of binding globulins, such as sex hormone-binding globulin and corticosteroid-binding globulin, which can influence hormone bioavailability. Clinical studies have consistently demonstrated that this combination in Kurvelo results in highly effective contraception when taken as directed. Comparative analyses show that Kurvelo’s mechanism aligns with other combined oral contraceptives utilizing levonorgestrel and ethinyl estradiol, with the 0.15 mg/30 mcg dosing offering a balance between efficacy and tolerability.

Pharmacological Actions

Suppression of ovulation by inhibiting the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
Alteration of cervical mucus viscosity, reducing sperm penetration and motility.
Modification of the endometrial lining to prevent implantation of a fertilized ovum.
Regulation of menstrual cycles via stabilization of the endometrium.
Increase in serum concentrations of sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin.
Reduction of follicular development through hypothalamic-pituitary axis feedback.
Estrogen component reduces breakthrough bleeding and contributes to cycle control.
Progestin-induced changes in tubal motility potentially reducing fertilization probability.
Hormonal modulation contributing to decreased menstrual blood loss and dysmenorrhea relief in some individuals.
Contraceptive maintenance via steady-state hormone levels when dosed daily at consistent intervals.

Therapeutic Or Clinical Uses

Prevention of pregnancy in women of reproductive potential.
Regulation of menstrual cycles and reduction of menstrual irregularities.
Management of symptoms related to hormonal contraception such as dysmenorrhea.
Contraceptive option for women seeking oral reversible birth control.
Contraceptive use in non-lactating women post-abortion or miscarriage (with timing considerations).
Alternative contraceptive for women requiring hormonal birth control with levonorgestrel and ethinyl estradiol.
Utility in women transitioning from other hormonal contraceptives (pills, patches, rings, implants, injections, IUDs).
Prevention of ovulation and associated hormonal fluctuations.
Support in family planning and reproductive health management.

Side Or Adverse Effects

Blood clots (venous thromboembolism, deep vein thrombosis, pulmonary embolism).
Stroke and myocardial infarction, especially in smokers and women over 35 years of age.
Nausea and vomiting, particularly during the first few months of use.
Breakthrough vaginal bleeding and spotting, especially during the initial three months.
Amenorrhea or oligomenorrhea (absence or irregularity of menstrual periods).
Breast tenderness, enlargement, or pain.
Headache, including migraine exacerbation or new onset.
Mood changes, including depression.
Elevated blood pressure and hypertension.
Gallbladder disease or exacerbation of pre-existing conditions.
Chloasma (melasma), characterized by dark patches on the skin.
Possible liver enzyme elevations and rare liver tumors (hepatic adenomas).
Fluid retention and edema.
Allergic reactions such as rash, urticaria, and angioedema.
Weight changes (gain or loss) and changes in appetite.
Changes in libido.
Tolerance issues with contact lenses due to corneal changes.
Gastrointestinal disturbances including abdominal pain and cramping.

Precautions

Assess personal and family history of thromboembolic or cardiovascular disease before initiating therapy.
Monitor blood pressure regularly during use, especially in women with hypertension risk factors.
Use caution in patients with a history of lipid disorders, hypertriglyceridemia, or pancreatitis risk.
Consider alternative contraception in women with uncontrolled dyslipidemia or severe hypertriglyceridemia.
Avoid use in women over 35 years who smoke due to elevated cardiovascular risk.
Monitor glycemic control in diabetic patients; contraindicated in diabetics over 35 years with complications.
Discontinue or withhold in presence of unexplained vaginal bleeding to rule out malignancy or other pathology.
Not recommended during breastfeeding due to potential reduction in milk production.
Advise use of backup contraception when taking enzyme-inducing drugs that decrease hormone levels.
Be vigilant for signs of depression, and discontinue if serious symptoms develop.
Patients with hereditary angioedema may experience exacerbation of symptoms.
Avoid concomitant use with Hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir due to risk of liver enzyme elevation.
Counsel patients regarding the lack of protection against HIV and other sexually transmitted infections.
Educate about potential for breakthrough bleeding and importance of adherence to dosing schedule.
Advise patients to avoid excessive sun exposure to decrease risk of chloasma.

Warnings

Increased risk of serious cardiovascular events, including thromboembolism, myocardial infarction, and stroke; risk heightened in women >35 years and smokers.
Discontinue immediately if arterial or venous thrombotic/thromboembolic events occur.
Do not initiate therapy in the immediate postpartum period; delay at least 4 weeks to reduce thromboembolic risk.
Contraindicated in women with current or history of breast cancer or hormone-sensitive malignancies.
Risk of liver dysfunction, including hepatic adenomas and elevated liver enzymes; discontinue if jaundice occurs.
Potential for increased blood pressure; monitor regularly and discontinue if hypertension worsens.
May exacerbate or induce migraine headaches, especially those with aura; contraindicated in such cases.
Do not use in patients with uncontrolled diabetes with vascular complications or long disease duration (>20 years).
Use caution with concomitant medications affecting liver enzyme metabolism; drug interactions may alter efficacy.
May cause gallbladder disease; history of pregnancy-related cholestasis increases risk.
Bleeding irregularities including breakthrough bleeding and spotting, especially in early treatment.
Depression and mood changes may occur; monitor patients with history of mood disorders closely.
Discontinue if unexplained vision changes or retinal vascular lesions develop due to possible thrombosis.
Potential carcinogenic risk with long-term use: slight increased risk of breast and cervical cancers reported.
Effect on binding globulins may alter thyroid or cortisol hormone therapy requirements.
Increased risk of serious adverse reactions if combined with Hepatitis C protease inhibitors; avoid coadministration.

Contraindication

Women over 35 years who smoke cigarettes due to elevated risk of cardiovascular events.
Known or suspected pregnancy; discontinue if pregnancy occurs.
Current or history of arterial or venous thrombotic/thromboembolic disorders (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction).
Cerebrovascular disease or coronary artery disease.
Thrombogenic cardiac valvular or rhythm diseases (e.g., bacterial endocarditis with valvular disease, atrial fibrillation).
Inherited or acquired hypercoagulopathies.
Uncontrolled hypertension or hypertension with vascular disease.
Diabetes mellitus with vascular complications, nephropathy, retinopathy, neuropathy, or long duration (>20 years) in women >35 years.
Migraine headaches with focal neurological symptoms or aura; any migraine headaches in women >35 years.
Current or history of breast cancer or other hormonally sensitive malignancies.
Liver tumors (benign or malignant), acute viral hepatitis, or severe (decompensated) cirrhosis.
Unexplained abnormal uterine bleeding.
Concomitant use with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, and glecaprevir/pibrentasvir due to risk of significant ALT elevations.

Drug Interactions

Enzyme inducers such as rifampin, carbamazepine, phenytoin, barbiturates, bosentan, efavirenz, griseofulvin, oxcarbazepine, topiramate, st. John's wort, and certain protease inhibitors can reduce plasma concentrations of levonorgestrel and ethinyl estradiol, potentially decreasing contraceptive effectiveness.
Co-administration with colesevelam decreases ethinyl estradiol systemic exposure; administration should be separated by at least 4 hours.
CYP3A4 inhibitors like ketoconazole, itraconazole, voriconazole, fluconazole, and grapefruit juice may increase plasma concentrations of contraceptive hormones, increasing risk of adverse effects.
HIV protease inhibitors (nelfinavir, ritonavir, darunavir/ritonavir, lopinavir/ritonavir, tipranavir/ritonavir) and some HCV protease inhibitors reduce systemic exposure of contraceptive hormones, compromising efficacy.
Non-nucleoside reverse transcriptase inhibitors (nevirapine) decrease contraceptive hormone levels, whereas others (etravirine) may increase them.
Atorvastatin and rosuvastatin increase systemic ethinyl estradiol exposure by 20-25%.
Concomitant use with lamotrigine decreases lamotrigine levels by inducing glucuronidation, possibly reducing seizure control.
Ethinyl estradiol-containing contraceptives elevate thyroxine-binding globulin and cortisol-binding globulin, potentially requiring dose adjustments of thyroid or corticosteroid replacement therapies.
Coadministration may alter systemic exposure of acetaminophen, morphine, salicylic acid, temazepam, cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole, necessitating dosage monitoring.
Do not use concurrently with Hepatitis C drug regimens containing ombitasvir/paritaprevir/ritonavir due to risk of significant liver enzyme elevations.
Drugs causing gastrointestinal disturbances such as vomiting or diarrhea may reduce absorption and contraceptive efficacy.
Backup contraceptive methods advised when starting or stopping interacting drugs and during enzyme inducer use plus 28 days post-inducer discontinuation.

Preparations Of The Drug

Kurvelo contains combination oral contraceptive tablets with 0.15 mg levonorgestrel and 30 mcg ethinyl estradiol per active tablet.
The medication pack comprises 21 light-orange active tablets and 7 pink inert (placebo) tablets to complete a 28-day regimen.
Active tablets are round, biconvex, 6mm in diameter, debossed with 'LU' on one side and 'U31' on the other.
Inert tablets are pink, round, biconvex, 6mm in diameter, debossed with 'LU' on one side and 'U32' on the other.
Inactive ingredients in active tablets include croscarmellose sodium, FD&C Yellow #6, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone.
Inactive ingredients in inert tablets include croscarmellose sodium, D&C Red #30, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
Packaged as three blisters of 28 tablets each in a carton.
Distributed by Lupin Pharmaceuticals, Inc., Baltimore, Maryland, USA; manufactured by Lupin Limited, Pithampur (M.P.), India.
Storage recommended at controlled room temperature (20°C to 25°C) with protection from light.
ADA codes and national drug codes (NDC) include 68180-844-71 for blister pack and 68180-844-73 for carton packaging.